This proposal seeks to develop mimics of naturally occurring ECM proteins with similar biologic functionality. The peptide mimics of interest for this proposal are polydepsipeptides (PDPs), also known as polyester amides. These polymers have properties characteristic of proteins by virtue of the ability to control the chemistry of side chain substituents. The side chains can be varied among a wide range of functionalities, resulting in a family of polymers with a host of possible molecular interactions, degradation characteristics and potential bioactivities. Expected outcomes of this project are the development of degradable materials with molecular specificity. Current techniques to develop peptide mimics rely on bulk chemistry with little variability in primary sequence or surface chemistry approaches with limitations on scale-up and clinical translation. PDPs provide a unique platform with advantages of both traditional degradable polymers and engineered peptide sequences. Because PDPs can be polymerized from a large, asymmetric six- membered ring, the side chains can be varied according to the choice of starting monomer resulting in an AB-type sequence. While this does not have the complexity of an engineered peptide, it has the advantage of potential bulk synthesis. Because the resulting polymer has sequence specificity, and based on our preliminary studies, shows relevant secondary structure, we propose to evaluate PDPs that can strongly bind the naturally occurring polyanion, heparin, for participation in polyelectrolyte complexation. Overall objective: Develop a virtual and synthetic library of polydepsipeptides consisting of alternating ester and amide linkages that can exhibit biologically relevant properties through controllable secondary structure. Based on the overall objective, three specific aims are outlined below for this project. Specific Aim 1: We propose to screen side chain substituents based on molecular modeling and dynamics simulations for relevant nanoscale structures and properties to facilitate heparin complexation. Specific Aim 2: A library of cyclic precursors will be fabricated using solid phase techniques for subsequent ring-opening polymerization and evaluation of secondary structure. Specific Aim 3: Candidate polydepsipeptides will be polymerized and evaluated for their ability to undergo polyelectrolyte complexation with heparin. We propose that alternating hydrophobic and charged functional groups will provide the appropriate nanoscale structure for assembly. PUBLIC HEALTH RELEVANCE: The overarching goal of this project is to transform the design of polymer-based therapeutics for millions who might otherwise suffer and die from heart disease. Using a rational design approach, the PI will implement a novel class of biomimetic cardiac therapeutics with the unique advantages of biologic specificity, degradability, minimally-invasive delivery, and a tailorable delivery platform. Biomaterials with nanoscale specificity have increasingly been explored for use in tissue engineering and regenerative medicine. Engineering nanostructure provides control over cell and tissue behavior that is not possible with traditional inert biomaterials. Current strategies often conform to a reductionist approach whereby natural tissue and protein structures are examined and recapitulated in a modified form. The current proposal seeks to perform a rational synthesis of materials with biologic activity based on a closed-loop approach of molecular modeling, monomer library synthesis, and subsequent testing of polymeric candidates. This type of bottom-up approach may serve as a model for the design and optimization of biomaterials with relevant bioactivity for use in cardiac therapy.